The Maillard reaction is a reaction which starts in a living body with an attack by a nucleophilic reaction with a free amino group present in a protein on an aldehyde group of a reducing sugar such as glucose to form a Schiff base which is called aldimine. Then, aldimine successively causes a rearrangement to form a more stable Amadori compound (non-enzymatic glycation). The Amadori compound further causes a series of reaction with other proteinous amino groups, thereby to form a brown fluorescent material and to cause a crosslinking between proteins. Historically, Maillard reported in 1912 that a mixed solution of an amino acid and a reducing sugar, when heated, is colored into brown (L. C. Maillard, Compt. Rend. Soc. Biol., 72, 599 (1912)) and, since then the reaction is called Maillard reaction. At that time, Maillard already suggested that the reaction could occur in a living body.
In 1968, Rabber et al found that hemoglobin A.sub.1C which is a very small fraction of hemoglobin is increased in the blood of diabetic patients (S. Rabber et al., Clin. Chim. Acta., 22, 296 (1968)] and further, it was found that the hemoglobin A.sub.1C was formed by bonding glucose to the N terminal valine of the hemoglobin .beta.-chain in the form of an Anadori rearrangement (V. J. Stevens, H. Vlassara, A Abati & A. Cerami, J. Biol. Chem., 252, 2998 (1977)), etc., and the occurrence of a non-enzymatic glycation in a living body was proved.
Recently, it has been confirmed that various bioproteins may undergo the Millard reaction. For example, it is reported that the amount of hemoglobin subjected to a glycation is increased thrice in a diabetic [E. C. Abraham et al, J. Lab. Clin. Med., 102, 187 (1983)].
Also, it is reported that the amount of glycation is increased in the serum albumin of diabetic patients (R. Dolhofer and O. H. Wieland, Diabetes, 29, 417 (1980)). Also, it is reported that fluorescence is increased in the skin collagen obtained from diabetic patients (Vincent M. Monnier et al, Proc. Natl. Acad. Sci. U.S.A., 81, 583 (1984)).
The non-enzymatic glycation is a phenomenon observed in a healthy person, but the accumulation of the brown fluorescent material is a protein having a delayed metabolic turnover rate and is markedly observed in aging and a diabetic state of increasing a blood sugar value. The reason therefor has been reported by Patrick et al that an accumulated amount of the Maillard reaction product is determined by a blood sugar value, the metabolic turnover rate of the target protein thereof, etc. (J. S. Patrick, S. R. Thorpe and J. W. Baynes, Journal of Gerontology, 45, 1, B18-23 (1990)).
The correlation between such a Maillard reaction product and various cause of diseases relating to diabetes and aging has been discussed. For example, it is reported that, when a serum protein which has been subjected to glycation is intravenously administered to mice for 12 weeks, a typical renal disorder in diabetes is caused (B. A. McVerry et al, The Lancet, 5, 738 (1980)). It is also considered that the non-enzymatic glycation of a nervous myelin protein takes part in one of the causes of the diabetic nervous disorder (V. M. Monnier et al, Clin. Endocrinol. Metab., 11, 431 (1982)).
An eyeball lens crystalline is a specific protein causing no metabolic turnover after being biosynthesized, and Cerami et al found that, when the crystalline undergoes the glycation, a colorless crosslinked compound having a disulfide linkage and a colored crosslinked compound having a fluorescence are formed (V. M. Monnier & A. Cerami, Science, 211, 491 (1981) and V. M. Monnier & A. Cerami, Biochim. Biophys. Acta., 760, 97 (1983)). When the crystalline undergoes glycation, polymerization, insolubilization, increase in fluorescence, and coloring in brown occur, closely similar to the change of the eyeball lens with aging (S. H. Chiou et al, J. Biol. Chem., 256, 5176 (1981)).
Collagen and elastin which are proteins constituting connective tissues are proteins showing very slow metabolic turnover and a combined product with glucose has been found in a renal glomerules base membrane, a skin, a tendon, etc. (V. M. Monnier et al, "Maillard Reaction in Food", Prog. Food Nutr. Sci., 5, 315, Pergamon Press, London). Brownlee et al showed that, in a diabetic rat, crosslinking of collagen increases in the wall of the blood vessel, thereby to accumulate a fluorescent material, and also that such a crosslinking occurs by a non-enzymatic mechanism (M. Brownlee et al., Science, 232, 1629 (1989)). The relation with hardening of the arterial wall has been also considered (H. Rosenburn et al, Biochem. Biophys., Res. Commun., 91, 498 (1979)).
As described above, it is considered that the Maillard reaction in a living body takes part in various diseases relating to diabetes and aging.